TROP2 Antibody-Drug Conjugates With Cleavable Linkers
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Solution Overview
Problem
There is a demand for new antibody-drug conjugates (ADCs) targeting TROP2 that offer high safety and efficacy for treating various cancers, as existing ADCs like DS-1062 and TRODELVY, while effective, could benefit from further improvements in safety and therapeutic potential.
Innovation Solution
Development of novel antibody-conjugated drug compounds with specific structures and linkers that enable targeted delivery of cytotoxins to TROP2-expressing cancer cells, utilizing self-immolative spacers and enzyme-cleavable sequences to enhance specificity and reduce off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ADCs like DS-1062 and TRODELVY are used to target TROP2, then cancer treatment efficacy is improved, but safety and therapeutic potential need further improvement
Solution Approach 1:
The patent modifies the linker structure parameters by incorporating self-immolative spacers and enzyme-cleavable sequences, changing the chemical and biological properties of the ADC to achieve both improved safety and expanded therapeutic potential for various TROP2-expressing cancers
Solution Approach 2:
The patent introduces self-immolative spacers and enzyme-cleavable sequences as intermediary elements in the linker, which mediate between the antibody and payload to enable controlled release and reduce off-target effects, thereby improving safety while maintaining efficacy
2Measurement precision
If self-immolative spacers and enzyme-cleavable sequences are used in linkers, then specificity and reduction of off-target effects are enhanced, but device complexity increases
Solution Approach 1:
The patent segments the linker into functional modules including self-immolative spacers and enzyme-cleavable sequences, allowing each segment to perform a specific function while collectively achieving high specificity and reduced off-target effects
Solution Approach 2:
The self-immolative spacer automatically performs its function of releasing the payload upon encountering the enzyme-cleavable sequence, eliminating the need for external intervention and simplifying the overall mechanism despite the increased structural complexity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The proposed compounds demonstrate enhanced efficacy in inhibiting TROP2-associated tumors, showing improved cytotoxicity and reduced toxicity to non-target cells, thereby offering a safer and more effective treatment option for cancers such as breast, gastric, and pancreatic cancers.
Implementation Method 1
L1 is Cleavable sequence 1 comprising an amino acid sequence which can be cleaved by enzyme
Data Source
AI summary
The present disclosure relates to an antibody, a payload and a linker molecule for targeting molecule-drug conjugate, and the corresponding conjugate, the preparation and use thereof.